中国科技论文统计源期刊 中文核心期刊
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
, 阎爱荣
, YAN Airong
目的 评估茚达特罗/格隆溴铵与沙美特罗/氟替卡松治疗中度至极重度慢性阻塞性肺疾病(COPD)的成本-效果,为临床用药决策提供依据。方法 利用Markov模型队列模拟分析法预估两种药物治疗COPD的远期效果和费用。结果 茚达特罗/格隆溴铵和沙美特罗/氟替卡松治疗每例COPD患者的平均费用分别为86 393.01元和81 537.16元,分别获得5.47和5.32个质量调整生命年(QALYs)。茚达特罗/格隆溴铵相较于沙美特罗/氟替卡松的增量成本效果比(ICER)为32 372.33元/QALY。结论 在意愿支付水平内,与沙美特罗/氟替卡松相比,茚达特罗/格隆溴铵治疗COPD的成本略高,效果略好。
Objective To assess the cost-effectiveness indacaterol/glycopyrrolate FDC in patients with moderate to very severe chronic obstructive pulmonary diseases (COPD) in China,and to provide a basis for clinical medication decisions. Methods Markov model cohort simulation was used to estimate the long-term efficacy and cost of two drugs for COPD. Results The average cost of indacaterol/glycopyrrolate FDC and salmeterol/fluticasone for the treatment of COPD were 86 393.01
开放科学(资源服务)标识码(OSID)
2018年慢性阻塞性肺疾病(chronic obstructive pulmonary diseases,COPD)全球倡议中,将COPD定义为“一种可防治的常见疾病,其特征为持续存在的呼吸道症状和气流受限,常与由有害颗粒或气体的显著暴露引起和(或)肺泡异常有关”[1]。中度以上COPD的全球患病率达10.1%[2],是目前世界第四大死因[3]。我国COPD患者数已达9990万例,约占全世界慢阻肺患者人数的25%[4]。目前,COPD的治疗仍以预防病情恶化为主,一旦出现COPD的急性加重(AECOPD)就会导致患者肺功能下降[5]、生活质量[6]及生存率降低[7]和住院次数增加[8],从而给我国医疗保健带来沉重的负担。吸入长效支气管扩张药不仅可以控制症状,同时也可以预防COPD的急性加重[9]。临床中COPD的治疗主要根据患者肺功能的下降程度来选择相应的支气管扩张药或是否加用糖皮质激素。长效的β受体激动药(long-acting beta agonists,LABA)联合吸入用糖皮质激素(inhaled glucocorticoids,ICS)的复方制剂在临床中应用广泛。虽然长期吸入ICS相对于全身应用ICS产生的不良反应较少,但仍然与肺炎的发生[10]和其他不良反应的发生风险[11]有关。研究表明,对于有急性加重病史的COPD患者,以固定剂量的LABA联合ICS(如沙美特罗/氟替卡松)与吸入用长效的M受体阻断药(LAMA)噻托溴铵产生的COPD加重率相似[12]。因此,对于有COPD急性加重史的患者以LABA联合LAMA来替代LABA联合ICS成为可能。这类复合制剂对于减轻中度至重度COPD患者的症状和降低未来风险具有重要作用[13]。2001年底英国葛兰素史克公司生产的沙美特罗/替卡松粉吸入剂在我国上市,因其疗效确切,在稳定期COPD的治疗中发挥着重要的作用。2016年发表的一项为期52周的随机、双盲、双模拟、非劣效性Ⅲ期临床试验(FLAME试验)表明,茚达特罗/格隆溴铵(indacaterol/glycopyrronium bromide,IND/GLY)对于预防COPD的加重比沙美特罗/氟替卡松(salmeterol/fluticasone,SFC)更有效[14]。
2013年欧盟委员会批准了诺华公司双支气管扩张药(IND/GLY)用于COPD的成人患者维持治疗。2017年该药正式获得中国食品药品监督管理总局的进口批准,成为中国首个获批的双支气管扩张药物。虽然我国治疗稳定期COPD的常用药物仍以LABA与ICS的复合制剂为主,但IND/GLY因其支气管扩张作用显著,患者依从性好,逐渐受到欢迎。目前,国外已有关于SFC与IND/GLY疗效与安全性的比较研究[14],并有多篇文献对其进行了药物经济学评价[15,16,17,18,19]。但是评价结果的成本来源于他国,并不能完全适用于我国国情,笔者将以中国医疗成本为基础,采用模型分析的方法来评估成本效果。Markov模型是当前最流行的决策分析方法之一,该模型纳入时间因素,适用于病情延续时间长、反复发作的慢性疾病[20]。笔者运用Markov状态转移模型模拟疾病的发展状态,以FLAME试验治疗COPD患者的临床数据为基础,结合中国的医疗成本,从全社会的角度对IND/GLY与SFC治疗稳定期COPD进行药物经济性评价。
Markov模型基本要素包括Markov状态、循环周期、模型概率、健康产出和成本以及循环终止条件。
样本参数来源于FLAME试验的样本人群,该人群的平均年龄65岁,男性占76.1%,初步诊断为中度、重度和极重度的COPD患者发生率分别为33.68%,58.61%和7.71%。给药方法为接受IND/GLY(110 μg/50 μg)每天1次吸入或SFC(50 μg/500 μg)每天两次吸入。以一秒用力呼气容积(forced expiratory volume in one scond,FEV1)占预计值的百分比及COPD的疾病发展进程设立中度(moderate)、重度(severe)、极重度(very severe)和死亡(death)4种Markov状态。除死亡状态外,其余3种Markov状态按照是否需要额外的医疗保健护理又会经历无恶化、非严重恶化和严重恶化的疾病发展过程。Markov状态转移模型见
以FLAMA试验中患者的平均年龄65岁作为模拟人群的初始年龄,模拟患者整个生命历程,以死亡作为终点。由于COPD是一种长期慢性疾病,其发生状态转移概率较小,周期长度可以设定为1年。与普通人群相比,COPD患者的死亡率较高,因此,建立20年循环的研究时限是合理的。
1.3.1 COPD各疾病状态间的转移概率 转移概率的确定是多状态Markov模型非常关键的一个环节。COPD的疾病进展依赖于患者疾病的初始严重程度和FEV1的年下降率。根据患者的年龄、身高、体质量、性别比例作出基线FEV1预计方程,从而可以推算出年龄为65岁的目标人群中中度、重度和极重度COPD人群的初始FEV1数值(即占预计值80%,50%和30%的FEV1数值),再依据FLAMA试验中得到的FEV1年改善值推算出随后20年的FEV1值,从而分别作出相应的回归方程。假设经过时间
表1 COPD不同健康状态下的转移概率
Tab.1 Transition probability of different GOLD health states
1.3.2 疾病恶化状态的转移概率 COPD的恶化定义为两种或两种以上的主要呼吸症状(包括呼吸困难、咳嗽、咯痰、胸闷或气短等)的急性加重,持续时间3 d及以上,需要门诊及住院治疗来缓解症状。本模型中只考虑需要进行医疗干预的恶化。非严重恶化指的是需要口服糖皮质激素和(或)使用抗菌药物治疗,但无需住院的患者。疾病恶化状态的转移概率推算需明确该状态下已知药物的转移概率及与目标药物的相对风险比例(RR)。HETTLE等[22]提出的噻托溴铵1个月的恶化率可计算噻托溴铵12个月的恶化风险。再从SPARK[23]和FLAME[14]试验得出,IND/GLY与噻托溴铵总恶化的RR为0.9,严重恶化的RR为1.16;SFC与IND/GLY非严重恶化的RR为1/0.83,严重恶化的RR为1/0.87。使用两种药物后不同健康状态的恶化概率见
表2 COPD不同健康状态下的恶化概率
Tab.2 Exacerbation probability of different GOLD health states
1.3.3 死亡概率 一项COPD对死亡率影响研究,证明FEV1基线值是死亡的独立危险因素,危险比为0.98[24]。该值表明,FEV1占预计值的百分比每增加1个单位,死亡风险为参考风险的98%。由于FEV1在COPD的疾病进展过程中呈下降趋势,因此使用了危险比的倒数(1/0.98),使FEV1占预计值的百分比每降低1个单位,死亡风险为参考死亡风险的1.02倍。除此之外,COPD死亡率还与国家人口死亡率及FEV1下降值相关[25]。死亡概率为依时变量,不同年龄段普通中国人群的死亡率来自中国第六次全国人口普查数据[26]。结合以上描述用以下公式来计算COPD的死亡概率:
死亡概率=(普通人群死亡率)×1.02FEV1占预计值的百分比相对下降值
由公式来看,在该模型中,死亡概率只与FEV1的下降程度相关,而与COPD急性加重无关。COPD死亡概率的计算结果见
表3 不同年龄COPD患者在不同健康状态下的死亡概率
Tab.3 Death probability of different GOLD health states
健康效用值是在所有健康状态中,不同的健康状态相对于完全健康的权重,是评价某种健康状况满意程度的指标,是反映个体健康状况的综合指数。每个健康状态效用值都处于0~1之间,0表示死亡,1表示完全健康。为了反映COPD患者的生活质量受损情况,将效用权重单独分配给每种疾病状态和每个恶化事件。本研究的健康效用值来源于UPLIFT试验的研究成果,用EQ-5D-3L量表来评估COPD患者的健康相关生活质量。中度、重度、极重度的健康效用值分别为0.787,0.750,0.647;非严重恶化效用减量倍数、严重恶化效用减量倍数的健康效用值分别为0.15,0.50;死亡的健康效用值为0[27]。
在没有恶化的情况下,COPD患者需要维持性治疗,成本估计项目来自于德国的一项研究[28],而单位项目的价格则取自于中国医疗保险(医保)数据库,以“元”为单位。以北京医保数据库中治疗COPD的项目价格来计算,2012年中度、重度、极重度COPD患者维持性治疗成本分别为411.51,574.59,912.54元,非严重恶化的治疗成本(即次均门诊费用)为567.01元,严重恶化的治疗成本为22 276.42元[29]。由于文献中调查得到的成本是所调查年份的金额,直接使用会产生偏差,因此根据中国消费者价格指数折算到2018年[30]。
因为笔者尚未查询到IND/GLY在我国的药品价格,所以选取自2013—2018年发表的6篇文献,成本数据来自瑞典、加拿大、法国、意大利、波兰、新加坡、英国和我国台湾地区等多个国家和地区,以文献中所列出的日用药成本按序排列后取中位数作为该药的每天成本。故而IND/GLY的日用药成本为2.02美元[19],换算为人民币为14.02元(1美元=6.939 5元),SFC的日用药成本来自于各省药品招标采购网站上公布的价格,取日均中位价为10.52元。各种疾病状态下的成本,包括维持治疗成本与药物成本见
表4 Markov模型中各个状态下的成本
Tab.4 Costs in the Markov model under different status
通过TreeAge Pro 2011建立Markov模型,成本和健康效果均采用5%的贴现率,并在阈值为我国2017年人均GDP(59 660元)下进行成本-效果分析,见
表5 IND/GLY 与 SFC成本效果分析结果
Tab.5 Results of cost-effectiveness analysis for IND/GLY versus SFC
结合本研究基线资料特征,分别对成本、RR值及贴现率进行一维敏感度分析。成本、RR值采用基线值同时升高或降低10%作为敏感度分析范围;按照《中国药物与经济学评价指南》[20]推荐,贴现率波动范围为0~8%。以2017年我国人均GDP 59 660元作为意愿支付值,结果见
多种药物被用于COPD的治疗。LAMA+LABA的综合疗法被推荐用于COPD的维持治疗,并已证实可以显著提高患者的肺功能[1]。IND/GLY可以改善患者肺功能和生活质量,与单一组分制剂相比能够更快速地缓解呼吸困难症状。在FLAME试验中,IND/GLY在预防COPD的急性加重方面也优于SFC[14]。REZA MALEKI-YAZDI等[15]采用了Monte-Carlo模拟方法来评估加拿大、法国、意大利和葡萄牙中度至重度COPD患者的IND/GLY和SFC成本效果分析。结果表明,在中度至重度COPD患者中IND/GLY更具有经济性。TEE等[16]评估了在新加坡医疗环境中,IND/GLY对于中重度COPD患者来说具有很高的成本效益。CHAN等[17]从中国台湾地区医护人员的角度来评估IND/GLY与SFC及噻托溴铵的成本效益,结论为在COPD的维持治疗中,IND/GLY与SFC或噻托溴铵相比更经济。BJERMER等[18]基于FLAME试验评估了瑞典COPD人群的IND/GLY与SFC的成本效益,结果显示对于呼吸困难指数(mMRC)≥2的中度到极重度且既往有急性加重史的COPD患者来说,是一种性价比较高的治疗方法。同样,PRICE等[19]将IND/GLY与SFC以及不同比例的IND+GLY作为瑞典医疗机构COPD患者的主要维持性治疗方法进行了比较。假设效能相同的条件下,与IND+GLY相比,IND/GLY使得每例COPD患者在第1年和第5年内分别节省85欧元和368欧元;与SFC相比,IND/GLY同样更具有经济性。
因本研究的成本数据只来源于北京城镇参保的COPD患者的费用信息,参保人员的医疗花费与全人群可能存在一定差异。此外,由于IND/GLY在中国药品价格不明,故药物成本数据来源于文献。因此,由于不同国家药品成本不同,从而可能会对经济性评价结果产生影响。两种药物之间的相对风险比例来源于试验结果,由于试验研究人群主要以欧美人群为主,亚洲人群占比小,可能会由于人种和试验条件的差异使得与中国真实人群的恶化相对危险度在数值上不一致。此外,本研究使用的疗效数据仅来自于1次临床试验,可能低估或高估了治疗的效果。
本研究结果表明,在中度至极重度COPD患者维持治疗中,与SFC相比,IND/GLY成本略高,效果略好,更具有经济性。
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BACKGROUND: A key feature of chronic obstructive pulmonary disease (COPD) is an accelerated rate of decline in forced expiratory volume in 1 second (FEV(1)), but data on the variability and determinants of this change in patients who have established disease are scarce. METHODS: We analyzed the changes in FEV(1) after administration of a bronchodilator over a 3-year period in 2163 patients. A random-coefficient model was used to evaluate possible predictors of both FEV(1) levels and their changes over time. RESULTS: The mean (+/-SE) rate of change in FEV(1) was a decline of 33+/-2 ml per year, with significant variation among the patients studied. The between-patient standard deviation for the rate of decline was 59 ml per year. Over the 3-year study period, 38% of patients had an estimated decline in FEV(1) of more than 40 ml per year, 31% had a decline of 21 to 40 ml per year, 23% had a change in FEV(1) that ranged from a decrease of 20 ml per year to an increase of 20 ml per year, and 8% had an increase of more than 20 ml per year. The mean rate of decline in FEV(1) was 21+/-4 ml per year greater in current smokers than in current nonsmokers, 13+/-4 ml per year greater in patients with emphysema than in those without emphysema, and 17+/-4 ml per year greater in patients with bronchodilator reversibility than in those without reversibility. CONCLUSIONS: The rate of change in FEV(1) among patients with COPD is highly variable, with increased rates of decline among current smokers, patients with bronchodilator reversibility, and patients with emphysema.
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Exacerbations occur commonly in patients with moderate or severe chronic obstructive pulmonary disease (COPD) but factors affecting their severity and frequency or effects on quality of life are unknown. We measured daily peak expiratory flow rate (PEFR) and daily respiratory symptoms for 1 yr in 70 COPD patients (52 male, 18 female, mean age [+/- SD] 67.5 +/- 8.3 yr, FEV1 1.06 +/- 0.45 L, FVC 2.48 +/- 0.82 L, FEV1/FVC 44 +/- 15%, FEV1 reversibility 6.7 +/- 9.1%, PaO2 8.8 +/- 1.1 kPa). Quality of life was measured by the St. George's Respiratory Questionnaire (SGRQ). Exacerbations (E) were assessed at acute visit (reported exacerbation) or from diary card data each month (unreported exacerbation). In 61 (87%) patients there were 190 exacerbations (median 3; range, 1 to 8) of which 93 (51%) were reported. There were no differences in major symptoms (increase in dyspnea, sputum volume, or purulence) or physiological parameters between reported and unreported exacerbations. At exacerbation, median peak flow fell by an average of 6.6 L/min (p = 0.0003). Using the median number of exacerbations as the cutoff point, patients were classified as infrequent exacerbators (E = 0 to 2) or frequent exacerbators (E = 3 to 8). The SGRQ Total and component scores were significantly worse in the group that had frequent exacerbations: SGRQ Total score (mean difference = 14.8, p < 0.001), Symptoms (23.1, p < 0.001), Activities (12.2, p = 0.003), Impacts (13.9, p = 0.002). However there was no difference between frequent and infrequent exacerbators in the fall in peak flow at exacerbation. Factors predictive of frequent exacerbations were daily cough (p = 0.018), daily wheeze (p = 0.011), and daily cough and sputum (p = 0.009) and frequent exacerbations in the previous year (p = 0.001). These findings suggest that patient quality of life is related to COPD exacerbation frequency.
[本文引用:1]
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OBJECTIVE: Exacerbations of COPD requiring hospital admission have important clinical and societal implications. We sought to investigate the incidence, recurrence, risk factors, and mortality of patients with COPD exacerbations requiring hospital admission compared with those without hospital admission during 3-year follow-up. Patients with COPD (N = 2,138) were identified from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) observational cohort. METHODS: An analysis of time to first event of hospital admission was performed using Kaplan-Meier curves and Cox proportional hazard regression adjusting for possible confounders. RESULTS: Of the 2,138 patients, 670 (31%) reported a total of 1,452 COPD exacerbations requiring hospital admission during the study period; 313 patients (15%) reported multiple events. A prior history of exacerbation of COPD requiring hospital admission was the factor associated with the highest risk of a new hospitalization for exacerbation (hazard ratio, 2.71; 95% CI, 2.24-3.29; P < .001). Other risk factors included more severe airflow limitation, poorer health status, older age, radiologic evidence of emphysema, and higher WBC count. Having been hospitalized for exacerbation significantly increased the risk of mortality (P < .001). CONCLUSIONS: Exacerbations of COPD requiring hospital admission occur across all stages of airflow limitation and are a significant prognostic factor of reduced survival across all COPD stages. Patients with COPD at a high risk for hospitalization can be identified by their past history for similar events, and other factors, including the severity of airflow limitation, poor health status, age, presence of emphysema, and leukocytosis. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00292552; URL: www.clinicaltrials.gov.
[本文引用:1]
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Inhaled corticosteroids (ICS) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease (COPD). However, little is known about the risk of associated infections. In a post hoc analysis of the TOwards a Revolution in COPD Health (TORCH) study, we analysed and identified potential risk factors for adverse event reports of pneumonia in this randomised, double-blind trial comparing twice-daily inhaled salmeterol (SAL) 50 microg, fluticasone propionate (FP) 500 microg, and the combination (SFC) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs. Despite a higher withdrawal rate in the placebo arm, after adjusting for time on treatment, a greater rate of pneumonia was reported in the FP and SFC treatment arms (84 and 88 per 1,000 treatment-yrs, respectively) compared with SAL and placebo (52 and 52 per 1,000 treatment-yrs, respectively). Risk factors for pneumonia were age > or =55 yrs, forced expiratory volume in 1 s <50% predicted, COPD exacerbations in the year prior to the study, worse Medical Research Council dyspnoea scores and body mass index <25 kg.m(-2). No increase in pneumonia deaths with SFC was observed; this could not be concluded for FP. Despite the benefits of ICS-containing regimens in COPD management, healthcare providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies.
[本文引用:1]
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| [11] |
While the pharmacological management of chronic obstructive pulmonary disease (COPD) has evolved from the drugs used to treat asthma, the treatment models are different and the two diseases require clear differential diagnosis in order to determine the correct therapeutic strategy. In contrast to the almost universal requirement for anti-inflammatory treatment of persistent asthma, the efficacy of inhaled corticosteroids (ICS) is less well established in COPD and their role in treatment is limited. There is some evidence of a preventive effect of ICS on exacerbations in patients with COPD, but there is little evidence for an effect on mortality or lung function decline. As a result, treatment guidelines recommend the use of ICS in patients with severe or very severe disease (forced expiratory volume in 1 second <50% predicted) and repeated exacerbations. Patients with frequent exacerbations - a phenotype that is stable over time - are likely to be less common among those with moderate COPD (many of whom are managed in primary care) than in those with more severe disease. The indiscriminate use of ICS in COPD may expose patients to an unnecessary increase in the risk of side-effects such as pneumonia, osteoporosis, diabetes and cataracts, while wasting healthcare spending and potentially diverting attention from other more appropriate forms of management such as pulmonary rehabilitation and maximal bronchodilator use. Physicians should carefully weigh the likely benefits of ICS use against the potential risk of side-effects and costs in individual patients with COPD.
[本文引用:1]
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| [12] |
RATIONALE: Exacerbations are key drivers of morbidity and mortality in chronic obstructive pulmonary disease (COPD). OBJECTIVES: We compared the relative efficacy of the long-acting inhaled bronchodilator/antiinflammatory combination (salmeterol/fluticasone propionate) 50/500 microg twice daily and the long-acting bronchodilator (tiotropium) 18 microg once daily in preventing exacerbations and related outcomes in severe and very severe COPD. METHODS: A total of 1,323 patients (mean age, 64 yr, post-bronchodilator FEV1, 39% predicted) were randomized in this 2-year, double-blind, double-dummy parallel study. MEASUREMENTS AND MAIN RESULTS: Primary endpoint was health care utilization exacerbation rate. Other endpoints included health status measured by St. George's Respiratory Questionnaire (SGRQ), mortality, adverse events, and study withdrawal. Probability of withdrawing from the study was 29% greater with tiotropium than salmeterol/fluticasone propionate (P = 0.005). The modeled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group (rate ratio, 0.967; 95% confidence interval [CI], 0.836-1.119]; P = 0.656). The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate versus tiotropium (difference 2.1 units; 95% CI, 0.1-4.0; P = 0.038). Mortality was significantly lower in the salmeterol/fluticasone propionate group; 21 (3%) of patients in this group died compared with 38 (6%) in the tiotropium group (P = 0.032). More pneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium (P = 0.008). CONCLUSIONS: We found no difference in exacerbation rate between salmeterol/fluticasone propionate and tiotropium. More patients failed to complete the study while receiving tiotropium. A small statistically significant beneficial effect was found on health status, with an unexpected finding of lower deaths in salmeterol/fluticasone propionate-treated patients. Clinical trial registered with www.clinicaltrials.gov (NCT 00361959).
[本文引用:1]
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| [13] |
BACKGROUND: Long-acting muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone. The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-1) (NCT01854645) and the Multi-Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate-to-Very Severe COPD (PINNACLE-2) (NCT01854658) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6-mug (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology in patients with moderate-to-very severe COPD. METHODS: These two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40-80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 mug, FF MDI 9.6 mug, or placebo MDI (all twice daily), or tiotropium 18 mug dry powder inhaler (once daily in PINNACLE-1 only [open-label active comparator]). Efficacy and safety were assessed. RESULTS: At week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE-1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE-2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms). CONCLUSIONS: We conclude that GFF MDI 18/9.6 mug demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate-to-very severe COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658; URL: www.clinicaltrials.gov.
[本文引用:1]
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| [14] |
BACKGROUND: Most guidelines recommend either a long-acting beta-agonist (LABA) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist (LAMA) as the first-choice treatment for patients with chronic obstructive pulmonary disease (COPD) who have a high risk of exacerbations. The role of treatment with a LABA-LAMA regimen in these patients is unclear. METHODS: We conducted a 52-week, randomized, double-blind, double-dummy, noninferiority trial. Patients who had COPD with a history of at least one exacerbation during the previous year were randomly assigned to receive, by inhalation, either the LABA indacaterol (110 mug) plus the LAMA glycopyrronium (50 mug) once daily or the LABA salmeterol (50 mug) plus the inhaled glucocorticoid fluticasone (500 mug) twice daily. The primary outcome was the annual rate of all COPD exacerbations. RESULTS: A total of 1680 patients were assigned to the indacaterol-glycopyrronium group, and 1682 to the salmeterol-fluticasone group. Indacaterol-glycopyrronium showed not only noninferiority but also superiority to salmeterol-fluticasone in reducing the annual rate of all COPD exacerbations; the rate was 11% lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (3.59 vs. 4.03; rate ratio, 0.89; 95% confidence interval [CI], 0.83 to 0.96; P=0.003). The indacaterol-glycopyrronium group had a longer time to the first exacerbation than did the salmeterol-fluticasone group (71 days [95% CI, 60 to 82] vs. 51 days [95% CI, 46 to 57]; hazard ratio, 0.84 [95% CI, 0.78 to 0.91], representing a 16% lower risk; P<0.001). The annual rate of moderate or severe exacerbations was lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (0.98 vs. 1.19; rate ratio, 0.83; 95% CI, 0.75 to 0.91; P<0.001), and the time to the first moderate or severe exacerbation was longer in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group (hazard ratio, 0.78; 95% CI, 0.70 to 0.86; P<0.001), as was the time to the first severe exacerbation (hazard ratio, 0.81; 95% CI, 0.66 to 1.00; P=0.046). The effect of indacaterol-glycopyrronium versus salmeterol-fluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count. The incidence of adverse events and deaths was similar in the two groups. The incidence of pneumonia was 3.2% in the indacaterol-glycopyrronium group and 4.8% in the salmeterol-fluticasone group (P=0.02). CONCLUSIONS: Indacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year. (Funded by Novartis; FLAME ClinicalTrials.gov number, NCT01782326.).
[本文引用:5]
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| [15] |
OBJECTIVE: The objective of this study was to assess the cost effectiveness of the dual bronchodilator indacaterol/glycopyrronium (IND/GLY) compared with salmeterol/fluticasone combination (SFC) in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) who had a history of one or no exacerbations in the previous year, in Canada, France, Italy, and Portugal. METHODS: A patient-level simulation was developed to compare the costs and outcomes of IND/GLY versus SFC based on data from the LANTERN trial (NCT01709903). Monte-Carlo simulation methods were employed to follow individual patients over various time horizons. Population and efficacy inputs were derived from the LANTERN trial. Considering the payers' perspective, only direct costs were included. Costs and health outcomes were discounted annually at 3.0 % for all countries. Unit costs were taken from publically available sources with all costs converted to euros (euro). The cost base year was 2015. Deterministic and probabilistic sensitivity analyses were undertaken to test the robustness of the model results. RESULTS: IND/GLY was found to be the dominant (more effective and less costly) treatment option compared with SFC in all four countries. The use of IND/GLY was associated with mean total cost savings per patient over a lifetime of euro6202, euro1974, euro1611, and euro220 in Canada, France, Italy, and Portugal, respectively. Sensitivity analysis showed that exacerbation rates had the largest impact on incremental costs and quality-adjusted life-years (QALYs). The probability of IND/GLY being cost effective was estimated to be >95 % for thresholds above euro5000/QALY. CONCLUSION: In patients with moderate to severe COPD, IND/GLY is likely to be a cost-effective treatment alternative compared with SFC.
[本文引用:2]
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| [16] |
INTRODUCTION: In light of the growing evidence base for better clinical results with the use of the dual bronchodilator indacaterol/glycopyrronium (IND/GLY) over inhaled corticosteroid-containing salmeterol/fluticasone combination (SFC), this study aimed to evaluate the cost-effectiveness of IND/GLY over SFC in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) who are at low risk of exacerbations, in the Singapore healthcare setting. METHODS: A previously published patient-level simulation model was adapted for use in Singapore by applying local unit costs. The model was populated with clinical data from the LANTERN and ECLIPSE studies. Both costs and health outcomes were predicted for the lifetime horizon from a payer's perspective and were discounted at 3% per annum. Costs were expressed in 2015 USD exchange rates. Uncertainty was assessed through probabilistic sensitivity analysis. RESULTS: Compared to SFC, use of IND/GLY increased mean life expectancy by 0.316 years and mean quality-adjusted life years (QALYs) by 0.246 years, and decreased mean total treatment costs (drug costs and management of associated events) by USD 1,474 over the entire lifetime horizon. IND/GLY was considered to be 100% cost-effective at a threshold of 1 x gross domestic product per capita. The cost-effectiveness acceptability curve showed that IND/GLY was 100% cost-effective at a willingness-to-pay threshold of USD 0 (additional cost) when compared to SFC. CONCLUSION: IND/GLY was estimated to be highly cost-effective compared to SFC in patients with moderate-to-severe COPD who are not at high risk of exacerbations in the Singapore healthcare setting.
[本文引用:2]
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| [17] |
Objective: The aim of this study was to evaluate the cost-effectiveness of the long-acting beta-2 agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilator indacaterol/glycopyrronium (IND/GLY) as a maintenance treatment for COPD patients from the perspective of health care payer in Taiwan. Patients and methods: We adopted a patient-level simulation model, which included a cohort of COPD patients aged >/=40 years. The intervention used in the study was the treatment using IND/GLY, and comparators were tiotropium or salmeterol/fluticasone combination (SFC). Data related to the efficacy of drugs, incidence of exacerbation, and utility were obtained from clinical studies. Direct costs were estimated from claims data based on the severity of COPD. The cycle length was 6 months (to match forced expiratory volume in 1 second [FEV1] data), and the time horizons included 1, 3, 5, 10 years, and lifetime. Deterministic and probabilistic sensitivity analyses were conducted to test the robustness of the model results. Costs were expressed in US dollars with a discount rate of 3.0%. Results: Compared to tiotropium and SFC, the incremental cost-effectiveness ratios (ICERs) per quality-adjusted life year (QALY) gained of patients treated with IND/GLY were US$5,987 and US$14,990, respectively. One-way sensitivity analysis revealed that the improvement in FEV1 provided by IND/GLY, the distribution of patients with regard to the severity of COPD, and acute exacerbation rate ratio were the key drivers behind cost-effectiveness. Adopting a willingness to pay of US$60,000 per QALY gained as the threshold, there was a 98.7% probability that IND/GLY was cost-effective compared to tiotropium. Similarly, there was a 99.9% probability that IND/GLY was cost-effective compared to SFC. Conclusion: As a maintenance treatment for COPD, we consider the dual bronchodilator IND/GLY as a cost-effective strategy when compared to either tiotropium or SFC.
[本文引用:2]
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| [18] |
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| [19] |
BACKGROUND: Indacaterol/glycopyrronium (IND/GLY) is a once-daily inhaled fixed-dose combination of indacaterol (IND), a long-acting beta2-adrenergic agonist (LABA), and glycopyrronium (GLY), a long-acting muscarinic antagonist (LAMA) for use as maintenance treatment to relieve symptoms of chronic obstructive pulmonary disease (COPD) in adults. OBJECTIVE: To determine the economic benefits of IND/GLY compared with the free combination of indacaterol and glycopyrronium (IND + GLY), and with the fixed-dose combination of salmeterol/fluticasone (SFC), in a moderate-to-severe COPD population with low-exacerbation risk. The model-based analysis extrapolated results up to lifetime time horizon and calculated costs per quality-adjusted life year. METHODS: Assuming equal efficacy, a cost-minimisation analysis compared IND/GLY vs IND + GLY using model inputs from the double-blind, randomised SHINE trial. The double-blind, randomised ILLUMINATE and TORCH trials were used to analyse cost-effectiveness versus SFC. To consider ICS-related pneumonia events, published odds ratio comparing an ICS-exposed group to a control group of COPD patients was used. Direct and indirect drug costs as well as drug acquisition costs (in Swedish Krona [SEK]) were derived from published Swedish sources. Cost and effects were discounted with 3%. Uncertainty was assessed by one-way and probabilistic sensitivity analyses (PSA). RESULTS: IND/GLY was cost-saving vs IND + GLY with incremental savings of SEK (EUR) 768 (85), and 3309 (368) per patient over one and five years. IND/GLY was found to be less costly and more effective compared to SFC with cost savings of SEK (EUR) 2744 (303), 8854 (976), 13,938 (1536), 27,495 (3031) and 43,033 (4744) over one, three, five, ten years and lifetime. The PSA indicated that all iterations produced dominant results for IND/GLY. CONCLUSION: IND/GLY is cost-minimising vs IND + GLY and dominates SFC in the maintenance treatment of COPD patients in Sweden. Encouraging dual bronchodilator therapy over an ICS-containing combination results in lower total costs and better outcomes compared to combination therapy including fluticasone in moderate-to-severe COPD patients with low exacerbation risk.
[本文引用:3]
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| [20] |
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PURPOSE: The fixed-dose dual bronchodilator combination (FDC) of tiotropium and olodaterol showed increased effectiveness regarding lung function and health-related quality of life in patients with chronic obstructive pulmonary disease (COPD) compared with the use of its mono-components. Yet, while effectiveness and safety have been shown, the health economic implication of this treatment is still unknown. The aim of this study was to assess the cost-utility and budget impact of tiotropium-olodaterol FDC in patients with moderate to very severe COPD in the Netherlands. PATIENTS AND METHODS: A cost-utility study was performed, using an individual-level Markov model. To populate the model, individual patient-level data (age, height, sex, COPD duration, baseline forced expiratory volume in 1 second) were obtained from the tiotropium-olodaterol TOnado trial. In the model, forced expiratory volume in 1 second and patient-level data were extrapolated to utility and survival, and treatment with tiotropium-olodaterol FDC was compared with tiotropium. Cost-utility analysis was performed from the Dutch health care payer's perspective using a 15-year time horizon in the base-case analysis. The standard Dutch discount rates were applied (costs: 4.0%; effects: 1.5%). Both univariate and probabilistic sensitivity analyses were performed. Budget impact was annually assessed over a 5-year time horizon, taking into account different levels of medication adherence. RESULTS: As a result of cost increases, combined with quality-adjusted life-year (QALY) gains, results showed that tiotropium-olodaterol FDC had an incremental cost-effectiveness ratio of euro7,004/QALY. Without discounting, the incremental cost-effectiveness ratio was euro5,981/QALY. Results were robust in univariate and probabilistic sensitivity analyses. Budget impact was estimated at euro4.3 million over 5 years assuming 100% medication adherence. Scenarios with 40%, 60%, and 80% adherence resulted in lower 5-year incremental cost increases of euro1.7, euro2.6, and euro3.4 million, respectively. CONCLUSION: Tiotropium-olodaterol FDC can be considered a cost-effective treatment under current Dutch cost-effectiveness thresholds.
[本文引用:1]
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| [22] |
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| [23] |
BACKGROUND: We evaluated the effect of dual, longacting inhaled bronchodilator treatment on exacerbations in patients with severe and very severe chronic obstructive pulmonary disease (COPD). METHODS: In this parallel-group study, 2224 patients (aged >/=40 years, Global Initiative for Chronic Obstructive Lung Disease stages III-IV, and one or more moderate COPD exacerbation in the past year) were randomly assigned (1:1:1; via interactive voice response or web system; stratified for smoking status) to once-daily QVA149 (fixed-dose combination of indacaterol 110 mug and glycopyrronium 50 mug), glycopyrronium 50 mug, or tiotropium 18 mug for 64 weeks. Assignment to QVA149 and glycopyrronium was double-blind; tiotropium was open-label. Efficacy was assessed in all patients randomly assigned to treatment groups who received at least one dose of study drug; safety was assessed in all patients who received at least one dose whether or not they were assigned to a group. The primary objective was to show superiority of QVA149 versus glycopyrronium for rate of moderate to severe COPD exacerbations (defined by worsening symptoms and categorised by treatment requirements) during treatment. This completed trial is registered at ClinicalTrials.gov, NCT01120691. FINDINGS: Between April 27, 2010, and July 11, 2012, 741 patients were randomly assigned to receive QVA149, 741 to receive glycopyrronium, and 742 to receive tiotropium (729, 739, and 737 patients, respectively, analysed for efficacy). QVA149 significantly reduced the rate of moderate to severe exacerbations versus glycopyrronium by 12% (annualised rate of exacerbations 0.84 [95% CI 0.75-0.94] vs 0.95 [0.85-1.06]; rate ratio 0.88, 95% CI 0.77-0.99, p=0.038). Adverse events (including exacerbations) were reported for 678 (93%) of 729 patients on QVA149, 694 (94%) of 740 on glycopyrronium, and 686 (93%) of 737 on tiotropium. Incidence of serious adverse events was similar between groups (167 [23%] patients on QVA149, 179 [24%] on glycopyrronium, and 165 [22%] on tiotropium); COPD worsening was the most frequent serious adverse event (107 [15%] patients on QVA149, 116 [16%] on glycopyrronium, 87 [12%] on tiotropium). INTERPRETATIONS: The dual bronchodilator QVA149 was superior in preventing moderate to severe COPD exacerbations compared with the single longacting antimuscarinic bronchodilator glycopyrronium, with concomitant improvements in lung function and health status. These results indicate the potential of dual bronchodilation as a treatment option for patients with severe and very severe COPD. FUNDING: Novartis Pharma AG.
[本文引用:1]
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| [24] |
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| [25] |
The aim of this study was to derive new spirometric reference equations for the English population, using the 1995/1996 Health Survey for England, a large nationally representative cross-sectional study. The measurements used were the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) of a sample of 6,053
[本文引用:1]
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| [26] |
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| [27] |
DOI:10.2147/CEOR
URL
[本文引用:1]
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| [28] |
INTRODUCTION: Indacaterol is a novel inhaled once-daily long-acting beta(2)-agonist (LABA) for the maintenance treatment of COPD that has been compared to existing inhaled monotherapies on a number of symptomatic endpoints in clinical studies. With constrained healthcare budgets, the objective of this analysis was to evaluate the cost-effectiveness of indacaterol 150 mug, the approved starting dose for maintenance therapy, from a German heath service perspective against the most widely used bronchodilator tiotropium, and the twice-daily LABA, salmeterol. METHODS: A Markov model was developed with the following main health states: Mild, Moderate, Severe, and Very Severe COPD, based on pre-bronchodilator FEV(1) measures reported in the indacaterol clinical trials, and death. Each disease severity health state had two associated health states for severe or non-severe exacerbation. The model considered patients with moderate to severe COPD, with a mean age of 64 years. The base case time horizon was three years, with discounting set at 3% for costs and benefits. Selected clinical inputs and health state utilities were derived from indacaterol clinical trials, while costs were based on publicly available drug prices and tariffs or published sources. Inputs describing disease progression were based on published data on the rate of FEV(1) decline. RESULTS: Point-estimates show that indacaterol 150 mug is dominant (lower total costs and better outcomes) against tiotropium and salmeterol. An alternative analysis comparing indacaterol 300 mug (maximum dose) against tiotropium, showed an incremental cost-effectiveness ratio (ICER) of approximately euro28,300 per QALY. CONCLUSION: Indacaterol is cost-effective compared to tiotropium and salmeterol.
[本文引用:1]
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| [29] |
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